Radiographic techniques such as scintigraphy, and the like, find application in biological and medical procedures for diagnosis as well as research. Scintigraphy involves the use of radiopharmaceuticals; i.e., compounds containing (or labeled with) a radioisotope (i.e. radionuclide) which upon introduction into a mammal become localized in specific organs, tissue, or skeletal material that are sought to be imaged. When the radiopharmaceutical is so localized, traces, plates, or scintiphotos of the existing distribution of the radionuclide may be made by various radiation detectors known in the art. The observed distribution of the localized radionuclide can then be used to detect the presence of pathological conditions, abnormalities, and the like. Radiopharmaceuticals are thus often referred to as radiodiagnostics.
In many cases, radiopharmaceuticals are prepared using target-specific chelating agents which provide a bridge connecting a radionuclide, such as a radioactive metal like technetium-99m, or the like, and a material which will temporarily localize in the organ, tissue, or skeletal material which is to be imaged. Typical chelating agents for such purposes are: polydentate ligands that form a 1:1 or 2:1 ligand:radioactive metal complex; macrocyclic ligands of appropriate ring size and preferably where all coordinating atoms are in a planar configuration; and bicyclic or polycyclic ligands that can encapsulate the radioactive metal.
It is a well established fact that the delivery of drugs, including radiopharmaceuticals, to the brain is often seriously limited by transport and metabolism factors and, more specifically, by the functional barrier of the endothelial brain capillary wall deemed the blood-brain barrier. Site-specific delivery and/or sustained delivery of drugs to the brain are even more difficult.
It has been previously suggested to deliver a drug species, specifically N-methylpyridinium-2-carbaldoxime chloride (2-PAM), into the brain, the active nucleus of which in and of itself constitutes a quaternary pyridinium salt, by way of the dihydropyridine latentiated prodrug form thereof. Such approach is conspicuously delimited to relatively small molecule quaternary pyridinium ring-containing drug species and does not provide the overall ideal result of brain-specific, sustained release of the desired drug, with concomitant rapid elimination from the general circulation, enhanced drug efficacy and decreased toxicity. Hence, no "trapping" in the brain of the 2-PAM formed in situ results, and obviously no brain-specific, sustained delivery occurs as any consequence thereof: the 2-PAM is eliminated as fast from the brain as it is from the general circulation and other organs. Compare U.S. Pat. Nos. 3,929,813 and 3,962,447; Bodor et al, J. Pharm. Sci., 67, No. 5, pp. 685-687 (1978); Bodor et al, Science, Vol. 190 (1975), pp. 155-156; Shek, Higuchi and Bodor, J. Med. Chem., Vol. 19 (1976), pp. 113-117. A more recent extension of this approach is described by Brewster, Dissertation Abstracts International, Vol. 43, No. 09, March 1983, p. 2910B. It has also been speculated to deliver, e.g., an antitumor agent, into the brain by utilizing a dihydropyridine/pyridinium redox carrier moiety therefor, but this particular hypothesis necessarily entails derivatizing the dihydropyridine/pyridinium carrier with a substituent itself critically designed to control the release rate of the active drug species from the quaternary derivative thereof, as well as being critically functionally coordinated with the particular chemical and therapeutic activity/nature of the antitumor drug species itself; Bodor et al, J. Pharm. Sci., supra. See also Bodor, "Novel Approaches for the Design of Membrane Transport Properties of Drugs", in Design of Biopharmaceutical Properties Through Prodrugs and Analogs, Roche, E. B. (ed.), APhA Academy of Pharmaceutical Sciences, Washington, D.C., pp. 98-135 (1976).
More recently, Bodor et al, Science, Vo. 214, Dec. 18, 1981, pp. 1370-1372, have reported on site-specific sustained release of drugs to the brain. The Science publication outlines a scheme for specific and sustained delivery of drug species to the brain, as depicted in the following Scheme 1: ##STR1## According to the scheme in Science, a drug [D] is coupled to a quaternary carrier [QC].sup.+ and the [D-QC].sup.+ which results is then reduced chemically to the lipoidal dihydro form [D-DHC]. After administration of [D-DHC] in vivo, it is rapidly distributed throughout the body, including the brain. The dihydro form [D-DHC] is then in situ oxidized (rate constant, k.sub.1) (by the NAD.revreaction.NADH system) to the ideally inactive original [D-QC].sup.+ quaternary salt which, because of its ionic, hydrophilic character, should be rapidly eliminated from the general circulation of the body, while the blood-brain barrier should prevent its elimination from the brain (k.sub.3 &gt;&gt;k.sub.2 ; k.sub.3 &gt;&gt;k.sub.7). Enzymatic cleavage of the [D-QC].sup.+ that is "locked" in the brain effects a sustained delivery of the drug species [D], followed by its normal elimination (k.sub.5), metabolism. A properly selected carrier [QC].sup.+ will also be rapidly eliminated from the brain (k.sub. 6 &gt;&gt;k.sub.2). Because of the facile elimination of [D-QC].sup.+ from the general circulation, only minor amounts of drug are released in the body (k.sub.3 &gt;&gt;k.sub.4); [D] will be released primarily in the brain (k.sub.4 &gt;k.sub.2). The overall result ideally will be a brain-specific sustained release of the target drug species.
Bodor et al have reported, in Science, their work with phenylethylamine as the drug model, which was coupled to nicotinic acid, then quaternized to give compounds of the formula ##STR2## which were subsequently reduced by sodium dithionite to the corresponding compounds of the formula ##STR3## Testing of the N-methyl derivative in vivo supported the criteria set forth in Scheme 1. Bodor et al speculated that various types of drugs might possibly be delivered using the depicted or analogous carrier systems and indicated that use of N-methylnicotinic acid esters and amides and their pyridine ring-substituted derivatives was being studied for delivery of amino- or hydroxyl-containing drugs, including small peptides, to the brain. No other possible specific carriers were disclosed.
Other reports of Bodor et al's work have appeared in The Friday Evening Post, Aug. 14, 1981, Health Center Communications, University of Florida, Gainesville, Fla.; Chemical & Engineering News, Dec. 21, 1981, pp. 24-25; and Science News, Jan. 2, 1982, Vol. 121, No. 1, page 7. These publications do not suggest any carrier systems other than the specific N-methyl and N-benzyl nicotinic acid-type carriers disclosed in the Science publication. Other classes of drugs as well as a few specific drugs are mentioned as possible candidates for derivatization; for example, steroid hormones, cancer drugs and memory enhancers are indicated as targets for possible future work, as are enkephalins, and specifically, dopamine and testosterone. The publications do not suggest how to link such drugs to the carrier, except possibly when the drugs are simple structures containing a single NH.sub.2 or, perhaps, simple structures containing a single OH, of the primary or secondary type, as is the case with phenylethylamine or testosterone. There is, for example, no suggestion of how one of ordinary skill in the art would form a drug-carrier combination when the drug has a more complicated chemical structure than phenylethylamine, e.g., dopamine or an enkephalin. For further details concerning the work with phenylethylamine, dopamine and testosterone, see also Bodor et al, J. Med. Chem., Vol. 26, March 1983, pp. 313-317; Bodor et al, J. Med. Chem., Vol. 26, April 1983, pp. 528-534; Bodor et al, Pharmacology and Therapeutics, Vol. 19, No. 3, pp. 337-386 (April 1983), and Bodor et al, Science, Vol. 221, July 1983, pp. 65-67.
In view of the foregoing, it is apparent that there has existed an acutely serious, long-standing need for a truly effective, generic but nonetheless flexible, method for the site-specific or sustained delivery, or both, of drug species to the brain. This need has been addressed in International Patent Application No. PCT/US83/00725 (filed by UNIVERSITY OF FLORIDA on May 12, 1983 and published under International Publication No. W083/03968 on Nov. 24, 1983), which provides such a generic method for site-specific, sustained delivery of drugs to the brain utilizing a dihydropyridine.revreaction.pyridinium salt type of redox carrier system. According to the PCT application, a drug (typically having a reactive --OH, --COOH or --NH.sub.2 group) can be coupled to a dihydropyridine.revreaction.pyridinium carrier; the lipoidal dihydro form of the drug-carrier system readily crosses the blood-brain barrier; the dihydropyridine moiety is then oxidized in vivo to the ideally inactive quaternary form, which is "locked in" the brain, while it is facilely eliminated from the general circulation; enzymatic cleavage of the "locked in" quaternary effects a sustained delivery of the drug itself to the brain, to achieve the desired biological effect. Diagnostic agents such as radiopharmaceuticals are generally disclosed in the PCT application as possible candidates for the carrier system, but the synthetic approach of that application, which utilizes the drug itself as the starting material, is not desirable when radioactive materials, especially relatively short-lived radionuclides, are involved. Moreover, in the case of radionuclides, the earlier objective of an ideally inactive form locked in the brain would not achieve the desired result. Thus, a serious need still exists for an effective general method for the site-specific and/or sustained delivery of a desired radionuclide to the brain.